Eine intrauterine Infektion ist eine ernstzunehmende Erkrankung mit möglicherweise schwerwiegenden Folgen für den Feten. Frühgeborene, die einer Chorioamnionitis ausgesetzt waren, haben jedoch eine geringere Mortalitätsrate mit biochemischen und strukturellen Veränderungen während der Lungenentwicklung. Vorhergehende experimentelle Arbeiten belegen die Initiierung einer Lungenreifung durch intraamniotisch verabreichtes Lipopolysaccharid. Hierbei wurde durch Aspiration der Amnionflüssigkeit eine fetale pulmonale Inflammationsreaktion in Gang gesetzt. Die Hypothese der vorliegenden Arbeit lautete, dass eine durch intravenös appliziertes Lipopolysaccharid induzierte fetale systemische Inflammation die intrauterine Lungenreifung ebenfalls beeinflusst. Die im Rahmen dieser Arbeit durchgeführten Versuche erfolgten an 21 fetalen Schafen mit einem Gestationsalter von 107 Tagen. Alle Tiere wurden zunächst mit intrauterinen Kathetern versehen. Nach einer Erholungsphase von 3 Tagen erhielten die Kontrolltiere (N=12) Kochsalzlösung und die Tiere der Versuchsgruppe (N=9) 100ng Lipopolysaccharid intravenös. Lungenstruktur und Lungenreifung der fetalen Schafe wurden mittels biochemischer und histologischer Untersuchungen nach 3 (N=5) und nach 7 (N=4) Tagen beurteilt. Die Infusion der Lipopolysaccharidlösung hatte zumindest innerhalb des Versuchszeitraums keinen Einfluss auf das Körpergewicht des Feten. Die systemische Entzündung trägt jedoch zu einer pränatalen Verletzung mit strukturellen pulmonalen Veränderungen bei. Sowohl eine Lungenreifung als auch eine gestörte strukturelle Lungenentwicklung traten nach einer kurzfristigen fetalen Inflammation ein. Die Konzentration an Interleukin-6 in der bronchoalveolären Lavage stieg 3 Tage nach Applikation des Lipopolysaccharids mehr als 40fach an. Sowohl die Prozessierung von Pro-Surfactant Protein (SP)-B zu reifem SP-B als auch erhöhte Konzentrationen an SP-B konnten nach 7 Tagen nachgewiesen werden. Ebenfalls war eine Steigerung des phosphorylierten STAT-3 im Lungengewebe zu erkennen. Die Ablagerung von Elastinfasern an Septierungsstellen der Alveolen wurde innerhalb von 3 Tagen nach Lipopolysaccharidapplikation negativ beeinflusst. Aus den Erkenntnissen dieser Arbeit könnten neue Therapieansätze sowohl für das Atemnotsyndrom des Frühgeborenen als auch der bronchopulmonalen Dysplasie resultieren, die eine Modulation der Entzündungsreaktion zum Ziel haben. Alle therapeutischen Ansätze werden einen Weg zwischen den positiven Effekten der Lungenreifung mit gesteigerter Compliance, reduzierter Alveolarwanddicke und vermehrtem prozessiertem SP-B und den schädlichen Einwirkungen auf die Lungenstruktur mit veränderter Elastinverteilung und kapillärer Leckage finden müssen. Bedauerlicherweise können die erhobenen Daten nicht klären, ob die einmalige Infusion von LPS eine anhaltende oder permanente Störung der alveolären Entwicklung hervorbringt. Die strukturellen Veränderungen des Lungengewebes, die denen einer BPD ähneln, lassen jedoch eine permanente Organschädigung befürchten.

Background Influenza virus infections in immunologically naïve children (primary infection) may be more severe than in children with re-infections who are already immunologically primed. We compared frequency and severity of influenza virus primary and re-infections in pre-school children requiring outpatient treatment. Methods Influenza-unvaccinated children 1–5 years of age presenting at pediatric practices with febrile acute respiratory infection < 48 h after symptom onset were enrolled in a prospective, cross-sectional, multicenter surveillance study (2013–2015). Influenza types/subtypes were PCR-confirmed from oropharyngeal swabs. Influenza type/subtype-specific IgG antibodies serving as surrogate markers for immunological priming were determined using ELISA/hemagglutination inhibition assays. The acute influenza disease was defined as primary infection/re-infection by the absence/presence of influenza type-specific immunoglobulin G (IgG) and, in a second approach, by the absence/presence of subtype-specific IgG. Socio-demographic and clinical data were also recorded. Results Of 217 influenza infections, 178 were due to influenza A (87 [49%] primary infections, 91 [51%] re-infections) and 39 were due to influenza B (38 [97%] primary infections, one [3%] re-infection). Children with “influenza A primary infections” showed fever with respiratory symptoms for a shorter period than children with “influenza A re-infections” (median 3 vs. 4 days; age-adjusted p = 0.03); other disease characteristics were similar. If primary infections and re-infections were defined based on influenza A subtypes, 122 (87%) primary infections (78 “A(H3N2) primary infections”, 44 “A(H1N1)pdm09 primary infections”) and 18 (13%) re-infections could be classified (14 “A(H3N2) re-infections” and 4 “A(H1N1)pdm09 re-infections”). Per subtype, primary infections and re-infections were of similar disease severity. Children with re-infections defined on the subtype level usually had non-protective IgG titers against the subtype of their acute infection (16 of 18; 89%). Some patients infected by one of the influenza A subtypes showed protective IgG titers (≥ 1:40) against the other influenza A subtype (32/140; 23%). Conclusions Pre-school children with acute influenza A primary infections and re-infections presented with similar frequency in pediatric practices. Contrary to expectation, severity of acute “influenza A primary infections” and “influenza A re-infections” were similar. Most “influenza A re-infections” defined on the type level turned out to be primary infections when defined based on the subtype. On the subtype level, re-infections were rare and of similar disease severity as primary infections of the same subtype. Subtype level re-infections were usually associated with low IgG levels for the specific subtype of the acute infection, suggesting only short-time humoral immunity induced by previous infection by this subtype. Overall, the results indicated recurring influenza virus infections in this age group and no or only limited heterosubtypic antibody-mediated cross-protection.

Background Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved survival in high-risk childhood leukemia but is associated with long-term sequelae such as impaired pulmonary function and reduced exercise capacity impacting quality of life. Methods A convenience sample of 17 patients after allo-HSCT (HSCT—12 male, age 15.7±6.7 years, time after HSCT 5.3±2.8 years) underwent pulmonary function testing, echocardiography, and an incremental exercise test on a bike. Physical activity and health-related quality of life were assessed by questionnaires (7-day physical activity recall, PEDS-QL). Seventeen healthy age- and gender-matched controls served as control group (CG) for results of pulmonary function and exercise testing. Results HSCT showed reduced pulmonary function (HSCT vs. CG: FEV1 90.5±14.0 vs. 108.0±8.7%pred; FVC 88.4±19.3 vs. 107.6±6.9%pred, DLCO 75.3±23.6 vs. 104.9±12.8%pred) and exercise capacity (VO2peak 89±30.8%pred, CG 98±17.5%pred; Wmax 84±21.7%pred, CG 115±22.8%pred), but no relevant cardiac dysfunction and a good quality of life (PEDS-QL mean overall score 83.3±10.7). Differences in peak oxygen uptake between groups were mostly explained by 5 adolescent patients who underwent total body irradiation for conditioning. They showed significantly reduced diffusion capacity and reduced peak oxygen uptake. Patients reported a mean time of inactivity of 777±159min/day, moderate activity of 110±107 min/day, hard activity of 35±36 min/day, and very hard activity of 23±22 min/day. A higher amount of inactivity was associated with a lower peak oxygen uptake (correlation coefficient tau −0.48, p=0.023). Conclusions This pilot study shows that although patients after allo-HSCT reported a good quality of life, regular physical activity and exercise capacity are reduced in survivors of stem cell transplantation, especially in adolescents who are treated with total body irradiation for conditioning. Factors hindering regular physical activity need to be identified and exercise counseling should be part of follow-up visits in these patients.

Background Immune thrombocytopenia (ITP) is an autoimmune disease associated with isolated thrombocytopenia, which is caused by an imbalance between platelet production and platelet destruction. Petechial and mucous membrane hemorrhages are characteristic of ITP, but life-threatening bleeding rarely occurs. Depending on the bleeding symptoms, ITP can be treated with glucocorticoids (GC), intravenous immunoglobulins (IVIG), or in severe cases, platelet transfusions. Mild bleeding does not necessarily require therapy. Using the German Surveillance Unit for rare Pediatric Diseases (ESPED) we conducted a prospective survey on ITP patients in all German Children's Hospitals between September 2018 and August 2019. We collected data on ITP, including the clinical course, therapy implementation recommendations (according to the Association of German Scientific Medical Societies guidelines), outcome, and influence of treatment regimens depending on the treating physician´s experience with ITP patients. Results Of the 287 recorded cases of children with ITP, 268 questionnaires were sent to the authors. Two hundred seventeen of the questionnaires fulfilled the inclusion criteria. ITP affected boys and girls similarly, and the median age of manifestation was 3.5 years. The main reasons for hospitalization were thrombocytopenia, bleeding signs, hematomas, and/or petechiae. Bleeding scores were ≤ 3 in 96% of children, which corresponded to a low-to-moderately low risk of bleeding. No life-threatening bleeding was documented. The most common therapies were IVIG (n = 59), GC (n = 33), or a combination of these (n = 17). Blood products (i.e., red blood cells, platelet concentrate, and fresh frozen plasma) were given to 13 patients. Compared to the established guidelines, 67 patients were over-treated, and 2 patients were under-treated. Conclusions Adherence to German ITP treatment guidelines is currently limited. To improve patient safety and medical care, better medical training and dissemination of the guidelines are required in line with targeted analyses of patients with serious bleeding events to identify potential risk constellations.

Background The spondylodysplastic Ehlers-Danlos subtype (OMIM #130070) is a rare connective tissue disorder characterized by a combination of connective tissue symptoms, skeletal features and short stature. It is caused by variants in genes encoding for enzymes involved in the proteoglycan biosynthesis or for a zinc transporter. Presentation of cases We report two brothers with a similar phenotype of short stature, joint hypermobility, distinct craniofacial features, developmental delay and severe hypermetropia indicative for a spondylodysplastic Ehlers-Danlos subtype. One also suffered from a recurrent pneumothorax. Gene panel analysis identified two compound heterozygous variants in the B4GALT7 gene: c.641G > A and c.723 + 4A > G. B4GALT7 encodes for galactosyltransferase I, which is required for the initiation of glycosaminoglycan side chain synthesis of proteoglycans. Conclusions This is a first full report on two cases with spondylodysplastic Ehlers-Danlos syndrome and the c.723 + 4A > G variant of B4GALT7. The recurrent pneumothoraces observed in one case expand the variable phenotype of the syndrome.